This is a continuing long-range study of the effects of purine antimetabolites on tumor cells and various normal tissues. Most of the studies are ongoing investigations involving several interrelated areas; 1) Adenosine deaminase (ADA) and its inhibition. The tight-binding inhibitor, deoxycoformycin (dCF) is under study in intact cells and whole animals. Recent evidence indicates that the nucleoside transport system plays a rate-limiting role in the inactivation of intracellular ADA by dCF; dCF will be used as a tool to analyze further the transport system. 2) Studies with 5'-methylthioadenosine phosphorylase (MTA-Pase). In the past year, we have identified this enzyme in several normal and tumor tissues and have shown that it liberates free adenine from a variety of 5'-substituted adenosines. An excellent inhibitor, 5'-chloroformycin has been identified. Countinuing studies will examine modulations in this enzyme in response to cell-cycle specific inhibitors, mitogen stimulation of lymphocytes, hepatectomy, etc. Possible cytotoxic effects from the formation of 5-substituted ribose phosphates, or from the release of adenine analogs, e.g., 2-fluoroadenine, are under study. 3) Effect of analog nucleosides on blood platelet aggregation and metabolism. In recent studies we have analyzed the effects of alterations in both the ribose and aglycone moieties of adenosine on the inhibition of platelet aggregation in response to agents such as ADP. Studies of this type will continue as new analogs are developed. 4) Antitumor effects of adenosine analogs. Certain adenosine analogs that are excellent substrates for ADA display markedly potentiated cytotoxicity if co-administered with an ADA inhibitor, e.g., dCF. Recent studies with several human colon and lung (oat cell) tumors have displayed synergistic effects between dCF and the adenosine analogs formycin and 8-azaadenosine. Accumulation of analog nucleotides in tissues has been demonstrated. These recent discoveries will be explored more fully.